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Long-term Effects of The Hyperglycemic Intrauterine Environment Diabetes, Obesity and Fetal Programming Pennington Biomedical Research Center April 22, 2010. David J. Pettitt, MD Sansum Diabetes Research Institute. Studies on Long-term Implications for the Offspring of Women with Diabetes.

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David J. Pettitt, MD Sansum Diabetes Research Institute

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Long-term Effects of The Hyperglycemic Intrauterine EnvironmentDiabetes, Obesity and Fetal ProgrammingPennington Biomedical Research CenterApril 22, 2010

David J. Pettitt, MD

Sansum Diabetes Research Institute


Studies on Long-term Implications for the Offspring of Women with Diabetes

  • Pima Indian Study - Type 2 in mothers

    • Obesity, IGT, type 2 in offspring

  • Chicago Diabetes in Pregnancy Center - Type 1 or GDM in mothers

    • Obesity, IGT in offspring

  • Danish Offspring of Diabetic Women - Type 1 or GDM in mothers

    • Obesity, IFG, IGT, type 2 in offspring

  • Exeter Studies - HNF-1α MODY in mother

    • Earlier age of onset of HNF-1α in offspring

  • SEARCH for Diabetes in Youth Study – Unspecified type in mother

    • Earlier age of onset of type 2 in offspring


and 1985

1985

1908*

Weight for Height for Pima Children in 1908 and 1985

Females

Males

Weight (kg)

Height (centimeters)

*Hrdlicka, 1908


Are Pima Data Relevant forOther Populations?

  • In 1965 they were thought to be unique

  • Now it’s clear that they were just showing us our future

  • Many other ethnic groups have followed the same pattern of progression through obesity to diabetes

  • All “unique” Pima findings have been replicated in other populations


Subject Groups


Subject Groups


Subject Groups


Mean Relative Weight for Height

by Age and Mother’s Diabetes

Normal Birth Weight (90-110 %)

Offspring of:

Nondiabetic

Future diabetic

Diabetic

Mean Relative Weight (%)

Mean Relative Weight (%)


Relative weight at age 10-14 years by mother’s pregnancy glucose

155

145

Relative Weight (%)

135

125

< 5.6

5.6-6.6

6.7-7.7

7.8-11.0

Diabetes

Mother's 2-hour glucose (mM)


Prevalence of Obesity* by Maternal Diabetes During Pregnancy

Offspring of:

Nondiabetic

Future diabetic

Diabetic

* ≥ 140 % standard


Mean BMI in Siblings by exposure to diabetes In Utero

Exposure to

Diabetes In utero


DPC Offspring of DM

Pima offspring of DM

Pima offspring of nonDM

Symmetry Index in Offspring from theDiabetes in Pregnancy Center* in Chicagoand in Pima Indians from Arizona

*Silverman et al. Diabetes 1991


Amniotic Fluid Insulin Concentration and Symmetry Index at Birth in Offspring of Diabetic Women (n=56)

p < 0.05

n=7

n=28

n=21

Metzger et al. Arch Dis Child 1990;65:1050


p < 0.05

p < 0.05

Metzger et al. Arch Dis Child 1990;65:1050

Amniotic Fluid Insulin Concentration and Symmetry Index at Age 6 Years in Offspring of Diabetic Women (n=56)

n=13

n=29

n=14


Prevalence of Overweight ( ) and Obesity ( ) in Offspring by Mother’s Diabetes Risk during Pregnancy

* Clausen TD et al.:JClinEndocrinolMetab. April 2010


Magnetic Resonance Image

of Pregnancy Complicated by Diabetes

Tight Control

Poorly Controlled

Jovanovic-Peterson L et al. Am J Perinatol. 1993;10:432-437


95% Confidence Interval

Age-adjusted Diabetes Incidence by Body Mass Index

2


Increasing Diabetes Prevalence

1905 – Diabetes not mentioned (Russell)

1908 – One diabetic Pima (Hrdlicka)

1940 – Diabetes frequency similar in Indians

And general U.S. population (Joslin)

1954 – Diabetes more common in Pimas (Cohen)

1978 – Diabetes common. Affects ½ of

Pimas  35 years old (Knowler)

Today – Diabetes prevalence increasing. Affects

Children and adolescents.

Childhood onset Type 2 diabetes in other

U.S. groups

Tomorrow - ????


Both

Mother

Father

Neither

Prevalence of Diabetes byAge and Parental Diabetes

Parental

Diabetes


2-hour Glucose by Age and Mother’s Diabetes

Offspring of:

2-hour Glucose (mM)


Adjusted 2-hour glucose at age 10-14 years by mother’s pregnancy glucose

8.0

7.0

2-Hour Glucose (mM)

6.0

5.0

< 5.6

5.6-6.6

6.7-7.7

7.8-11.0

Diabetes

Mother's 2-hour glucose (mM)


Prevalence of Diabetes by Maternal Diabetes During Pregnancy

Offspring of:


Sib Pairs Discordant for Diabetes and for Intrauterine Exposure to Diabetes

Dabelea et al. Diabetes 2000


Prevalence of IGT in Offspring of Diabetic Mothers Diabetes in Pregnancy Center* in Chicago

10 to 16

* Silverman: Diabetes Care. 1995


Prevalence of Type 2 Diabetes/IGT/IFG in Offspring by Mother’s Diabetes Risk during Pregnancy

* Clausen TD et al.: Diabetes Care. Feb 2008


Mean age of MODY (HNF-1α) diagnosis by maternal diabetes in pregnancy

p<0.0001

Mother

Stride & Hattersley, Diabetes Care 2002;25


Mean age of MODY (HNF-1α) diagnosis by maternal diabetes in pregnancy or paternal age of diagnosis.

p<0.0001

p=0.77

Father

Mother

Stride & Hattersley, Diabetes Care 2002;25


Age of Onset of Type 2 Diabetes by Exposure to Diabetes in Utero

Data from SEARCH for Diabetes in Youth Study


Age of Onset of Type 2 Diabetes by Paternal Diabetes

Data from SEARCH for Diabetes in Youth Study


Diabetes in Pregnancy:Vicious Cycle

Mother with

Diabetes

Child or Woman

With Diabetes

Infant of

Diabetic Mother


Impaired Glucose Tolerance

Abnormal GTT During Pregnancy According to The Mother’s Pregnancy Glucose

Diabetes


(Left) & Attributable Risk (Right)

Increasing Diabetes During Pregnancy in Pima Indians: Percent exposed

Dabelea et al. Diabetologia 1998


Prevalence of Type 2 Diabetesby Age in 3 Time Periods


Other Early Life Risk Factors


Metabolic Syndrome by Birth Weightin Men aged 64 years

p for trend < 0.001

Barker et al. Diabetologia 1993


Age-adjusted Diabetes Prevalence

By Birth Weight (age 20-39 years)

McCance DR et al. BMJ, 1994


Prevalence of Diabetesby Birth Weight

Birth Weight (kg)


Prevalence of Diabetes by Birth Weightin 15-24 year old Women During Pregnancy


Prevalence of Diabetes by Birth Weight in25-34 year old Pima Women During Pregnancy

Pettitt & Knowler, Diabetes Care, 1998


Prevalence of GDM by Birth Weightof African American Women in Washington State

Williams et al. Ped & PerinatEpi, 1999


Prevalence of GDM by Birth Weight in Norwegian Women (n=138,714)

Egeland et al. BMJ, 2000


Prevalence of GDM by Birth Weightof Women in New York State (n=23,314)

Innes et al. JAMA, 2002


Breast Fed*

Bottle Fed

Prevalence of Diabetesby Infant Feeding

*  2 months


Adjusted* Prevalence of Diabetes

Odds ratio=0.42

(95% c.i.=0.18-0.96)

*Adjusted for age, birth date, sex, obesity, birth weight

parental diabetes and maternal diabetes in pregnancy


Percent of youth (age 15 ± 2.7 yr) Ever Breastfed

Type 2 diabetes Control

Mayer-Davis EJ et al. Diabetes Care 2008.


Prevalence of DiabetesDuring Pregnancy

Breast Fed

Yes No


Adjusted* Prevalence of Diabetes

Breast Fed

Yes No

*Adjusted for age, birth date, sex, birth weight, parental diabetes


Adjusted* Prevalence of Diabetes

Breast Fed

Yes No

*Adjusted for age, sex, parental diabetes


Diabetes in Pregnancy:Vicious Cycle

Mother with

Diabetes

New Diabetes

Sources

Child or Woman

With Diabetes

Infant of

Diabetic Mother


Summary

  • Diabetes in Pregnancy has long-lasting effects on the offspring:

    • More obesity

    • More diabetes

    • More gestational diabetes

  • Vicious Cycle

    • Diabetes begets Diabetes

    • Diabetes from other sources enter the cycle


BMI in Offspring according to whether

Mother, Father or Both are overweight.

Labayen I et al. Diabetes Care, April 2010


Skin Fold Thickness in Offspring according to whether

Mother, Father or Both are overweight.

Labayen I et al. Diabetes Care, April 2010


Adjusted* Prevalence of Diabetesby Breast and Bottle Feeding


Adjusted* Prevalence of Diabetesby Duration of Breast Feeding

*Adjusted for age, sex, birth weight, parental diabetes and maternal diabetes in pregnancy


Type 1 & Type 2 Diabetes

Gestational Diabetes

Fuel-Mediated Effects in Utero

Body Size-

Metabolic

Organ

Behavioral

Weeks of Pregnancy

Adapted from Freinkel: Diabetes 1980;29:1023


Studies with Data on Long-term Implications for the Offspring

  • Obesity & Diabetes

    • Pima Indian Study

  • Obesity & IGT/Diabetes

    • Chicago Diabetes in Pregnancy Center

    • Offspring of Danish Women

  • Age of onset

    • Exeter MODY Studies

    • SEARCH for Diabetes in Youth Study


Waist Circumference in Offspring according to whether

Mother, Father or Both are overweight.

Labayen I et al. Diabetes Care, April 2010


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